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Conditions

RAC2-associated combined immunodeficiency

RAC2-associated combined immunodeficiency is a rare genetic condition causing early-onset recurrent infections due to lymphopenia.

Overview

Ras-related C3 botulinum toxin substrate 2 (RAC2)-associated combined immunodeficiency is a rare primary immunodeficiency condition caused by dysfunction of RAC2, a small GTPase protein that plays a crucial role in immune cell function and cytoskeletal formation. Dysfunction leads to a spectrum of symptoms, varying from severe combined immunodeficiency (SCID) to recurrent infections presenting in adolescence.

Clinical features

RAC2-associated combined immunodeficiency is associated with two similar overlapping clinical phenotypes. Both present at an early age with recurrent infections due to reduced neutrophil chemotaxis.

In the most severe phenotype, patients present with features of SCID, a life-threatening condition resulting from severely impaired T-cell function. Typical infections include severe pneumonia or sepsis due to opportunistic pathogens such as Pneumocystis jiroveci, Pseudomonas sp, Candida sp and cytomegalovirus. Infections tend to be persistent and invasive despite conventional treatment. Vaccine-strain infection following administration of live vaccinations, such as BCG, may also occur. Viral infections may occur, particularly varicella, which can be life-threatening. Other features include impaired wound healing, such as delayed separation of the cord.

In some patients, presentation is later in life, with recurrent infections, progressive lymphopenia and impaired wound healing.

All patients have combined B- and T-cell immunodeficiency, progressive T-cell lymphopenia and hypogammaglobulinaemia.

Genomics

RAC2-associated combined immunodeficiency is caused by monoallelic pathogenic genetic variants in the RAC2 gene, located on the long arm of chromosome 22 (22q13.1). There is a pseudogene for RAC2 on the same chromosome, which should be considered during genomic analysis. The gene encodes RAC2, a small GTPase involved in immune cell development and cytoskeletal reorganisation.

Pathogenic variants in RAC2 may have a dominant gain-of-function effect. This mechanism of action has been demonstrated to cause SCID phenotype. These variants are typically missense.

Loss-of-function monoallelic variants have also been described to cause atypical neutrophil chemotaxis, with a phenotype of recurrent infections with impaired wound healing.

Incomplete penetrance has been seen in this condition, and there is considerable variability even within affected families.

Diagnosis

RAC2-associated combined immunodeficiency can be diagnosed following clinical evaluation or through newborn blood spot screening using the T-cell receptor excision circles assay. Where either is suggestive of SCID, laboratory evaluation is required. Patients may have a family history of immunodeficiency.

In laboratory tests:

  • full blood count may show reduced lymphocyte count;
  • lymphocyte subset testing may show absent or very low levels of T, B and/or NK cell count – that is, T-B-NK- phenotype – though this is variable;
  • immunoglobulin levels show reduced antibody responses (IgG levels may be reflective of maternal levels in infants less than six months old);
  • T-cell proliferation assay shows impaired response;
  • neutrophil function tests may be impaired, such as reduced chemotaxis.

Genetic testing confirms the diagnosis and differentiates RAC2-associated combined immunodeficiency from other causes of primary immunodeficiency. For information about testing, see ‘Infant or child with severe, recurrent, persistent and/or unusual infections‘.

RAC2-associated combined immunodeficiency may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

Inheritance and genetic counselling

RAC2-associated combined immunodeficiency is a rare genetic condition caused by monoallelic (heterozygous) pathogenic genetic variants in the RAC2 gene. It is inherited in an autosomal dominant pattern.

  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
  • Incomplete penetrance can occur (that is, not everyone who has the variant develops the disease), and is commonly seen with RAC2 variants.

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate. Note that de novo variants may also arise.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

RAC2-associated combined immunodeficiency may present early with features of SCID, which is a fatal condition unless definitive treatment is undertaken to reconstitute the immune system.

Immediate management principles involve treating infection and the prevention of opportunistic infections. This includes:

  • no live vaccinations;
  • aggressive treatment of infections, including with anti-fungal and anti-viral agents;
  • isolation from exposure to pathogens;
  • immunoglobulin replacement;
  • parenteral nutrition; and
  • irradiated, cytomegalovirus negative blood products, if required.

The primary curative treatment is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from the patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HSCT soon after birth tend to have the best outcomes with fewer complications.

For patients presenting later in life, treatment focuses on infection treatment and prevention. HSCT should also be considered in adults.

RAC2-associated combined immunodeficiency may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 01/08/2025
  • Next review due: 01/08/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay